- High blood pressure in the lungs, known as pulmonary arterial hypertension (PAH), is a rare disorder. Some people have disease-associated PAH and some have PAH from an unknown cause. Researchers want to follow the natural history of all PAH patients to understand how PAH progresses in order to discover targets for future research into new treatments. To further identify treatment targets, they will compare healthy volunteers to patients with PAH.

Objectives:

- To study the natural history of PAH.

Eligibility:

Individuals at least 18 years of age who have PAH.

Healthy volunteers at least 18 years of age.

Design:

Participants with PAH will have periodic visits to the National Institutes of Health Clinical Center. After the first visit, they will return in 6 months and then yearly or every other year for as long as the study continues.

The first visit will take up to 3 days. It will involve the following tests:

Physical exam and medical history

Blood and urine samples

Heart and lung function tests and imaging studies

Six-minute walk test

Questions about exercise and physical activity

Healthy volunteers will have only one visit to the Clinical Center, during which they will undergo screening tests, and complete many of the same tests as patients with PAH

Pulmonary arterial hypertension (PAH) is a rare disorder associated with poor survival. Endothelial dysfunction resulting from 1) genetic susceptibility, and 2) a triggering stimulus that initiates pulmonary vascular injury, the two-hit hypothesis, appears to play a central role both in the pathogenesis and progression of PAH. Inflammation appears to drive this dysfunctional endothelial phenotype, propagating cycles of injury and repair in genetically susceptible patients with idiopathic PAH (IPAH) and patients with disease-associated PAH. However, despite mounting evidence of vascular inflammation in patients with PAH, detailed phenotypic studies are lacking on the temporal evolution of this process and its contribution to right ventricular (RV) and pulmonary vascular remodeling. We hypothesize that a detailed characterization of the temporal evolution of vascular inflammation in PAH and its impact on RV and pulmonary vascular function will add prognostic value to traditional measures of disease severity and suggest novel therapeutic targets for future research.

Objectives:

Patients with IPAH and disease-associated PAH will be recruited to the NIH and enrolled in this natural history study investigating the ability of circulating markers of vascular inflammation as well as high-resolution cardiac magnetic resonance imaging (MRI) to accurately stage severity of disease and/or predict clinically relevant outcomes.

Methods:

The total population for the study will be 150 PAH subjects and approximately 55 age and gender matched controls (i.e. each healthy volunteer is matched to less than or equal to 3 PAH subjects).

Plasma markers of endothelial inflammation, PBMC expression profiles, and high-resolution cardiac MRI will also be studied in age and gender matched controls to define normal ranges and variability for each of these novel assessments. Comparison of these results to PAH subjects at baseline will be used to determine the degree to which these investigative tests distinguish PAH patients from healthy subjects. Likewise, baseline clinical evaluations of PAH subjects will be used to examine whether any novel test (inflammatory markers, or cardiac MRI), accurately classifies patients according to their disease severity. In addition, these tests will be investigated prospectively for their ability to predict PAH disease progression. Disease progression will be defined prospectively as a decrease in the 6-minute walk distance of greater than or equal to10% from baseline or clinical worsening requiring an escalation in therapy, hospitalization due to right heart failure, transplantation or death.

Additional plasma will be collected from PAH subjects and age/gender matched control subjects. This material will be used to probe for new biomarkers and inflammatory factors using discovery based approaches (i.e. Proteomics and pulmonary artery endothelial cell bioassay).

Eligibility

Ages Eligible for Study:

18 Years to 99 Years (Adult, Senior)

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Criteria

INCLUSION AND EXCLUSION CRITERIA FOR PAH SUBJECTS

Inclusion Criteria for PAH Subjects:

The following parameters on RHC are required to meet the hemodynamic definition of PAH (NYHA/WHO Group I PH):

mean pulmonary artery pressure of greater than 25 mmHg at rest,

pulmonary capillary wedge pressure of less than or equal to 15 mmHg (or a left ventricular end-diastolic pressure of less than or equal to 12mmHg) and

For patients with suspected PAH (Group I PH) who have not undergone a RHC and/or additional testing to confirm the diagnosis, this testing will be completed as clinically indicated under a procedural consent. If clinically indicated (diagnostic) testing indicates that the subject with suspected PAH does not in fact meet standard criteria for PAH (Group I PH), then the subject will be removed from the study.

Exclusion Criteria for PAH Subjects:

Pregnant or breastfeeding women (all women of childbearing potential will be required to have a screening urine or blood pregnancy test)

Age less than 18 years

Inability to provide informed written consent for participation in the study

INCLUSION AND EXCLUSION CRITERIA FOR HEALTHY CONTROL SUBJECTS

Inclusion Criteria for Control Subjects

Any healthy man or woman who is the appropriate age and gender for matching to a PAH patient

Must be eligible for MRI and Gadolinium Based MRI studies

Must be eligible for CT and Iodine Based Contrast CT studies

Exclusion Criteria for Healthy Control Subjects

Current pregnancy or breastfeeding (All women of childbearing potential will be required to have a screening urine or blood pregnancy test)

Electrocardiographic evidence of clinically relevant heart disease

Symptoms of coronary or cardiac insufficiency

More than one major risk factor for coronary artery disease (excluding age and gender)

Systemic hypertension that is not well controlled (i.e. blood pressure at the time of screening greater than or equal to140/90 mmHg) in adults < 60 years old or greater than or equal to 150/90 mmHg in adults 60 years or older) on medications. Subjects taking > 2 anti-hypertensive medications will be excluded irrespective of their current blood pressure at time of screening

Active tobacco use (> 6 months) in the past ten years, any tobacco use within 3 months prior to the screening evaluation or any tobacco use prior to completion of the study

Inability to provide informed written consent for participation in the study

History of recreational drug use with the exception of marijuana (as long as marijuana use was > 3 months from the time of study screening).

Exclusion Criteria for MRI in Healthy Control Subjects and Subjects with PAH

These contraindications include but are not limited to the following devices or conditions:

Implanted cardiac pacemaker or defibrillator

Cochlear Implants

Ocular foreign body (e.g. metal shavings)

Embedded shrapnel fragments

Central nervous system aneurysm clips

Implanted neural stimulator

Any implanted device that is incompatible with MRI

Unsatisfactory performance status as judged by the referring physician such that the subject could not tolerate an MRI scan. Examples of medical conditions that would not be accepted would include unstable angina and severe dyspnea at rest

Exclusion Criteria for Cardiac Computed Tomography in Healthy Control Subjects and Subjects with PAH:

1) Subjects with a condition precluding entry into the scanner (e.g. morbid

obesity, claustrophobia, etc.)

Exclusion Criteria for Iodine Based Contrast CTA Studies Only:

Serum creatinine > 1.4 mg/dL

History of multiple myeloma

Use of metformin-containing products less than 24 hours prior to contrast administration

History of significant allergic reaction to CTA contrast agents despite premedication with diphenhydramine and prednisone

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study.
To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.
For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01730092